Bisamidoximes: Synthesis and complexation with iron(III)

Article abstract of DOI:10.1071/CH07157

Bisamidoximes have been synthesized by the reaction of 4- methylbenzohydroximoyl chloride with 1,2-diaminoethane, 1,3-diaminopropane, 1,4-diaminobutane, and 3,3?-diamino-N-methyl-dipropylamine. A monoamidoxime and a trisamidoxime were also prepared in the

Full text of DOI:10.1071/CH07157

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2007, 60, 685–690
Bisamidoximes: Synthesis and Complexation with Iron(III)
James E. Johnson,A,E Carol Carvallo,A Debra D. Dolliver,B Natalia Sanchez,A
Vilma Garza,A Diana C. Canseco,A Gordon L. Eggleton,C
and Frank R. FronczekD
ADepartment of Chemistry and Physics, Texas Woman’s University, Denton, TX 76204-5859, USA.
BDepartment of Chemistry and Physics, Southeastern Louisiana University, Hammond, LA 70402, USA.
CDepartment of Physical Sciences, Southeastern Oklahoma University, Durant, OK 74701-0609, USA.
DDepartment of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA.
ECorresponding author. Email: jjohnson@mail.twu.edu
Bisamidoximes have been synthesized by the reaction of 4-methylbenzohydroximoyl chloride with 1,2-diaminoethane,
1,3-diaminopropane, 1,4-diaminobutane, and 3,3ꢀ-diamino-N-methyl-dipropylamine. A monoamidoxime and a trisami-
doxime were also prepared in the present work by the reaction of 4-methylbenzohydroximoyl chloride with N,N-
dimethylethylenediamine and tris(2-aminoethyl)amine. Single crystal X-ray structures of three of the bisamidoximes
have shown that the two amidoxime moieties have the Z configuration in all three compounds. Job’s method of continuous
variations showed that three of the bisamidoximes prepared in this work form 1:1 complexes with iron(iii) and therefore
are acting as tetradentate ligands.
Manuscript received: 17 May 2007.
Final version: 1 August 2007.
Introduction
complex with iron(iii), has been the primary chelator used to
rid the body of iron in these overload syndromes.[4] Although it
has been proved to be effective and to display good long-term
tolerability, it is expensive and relatively inefficient.[3–5]
Recently, it has been discovered that hydroxamic acids can
be used as histone deacetylase (HDAC) inhibitors. These com-
pounds have antiproliferative activity and have been shown to be
useful therapeutic agents.[6–8] Octanedioic acid hydroxyamide
phenylamide (2, suberoylanilide hydroxamic acid, SAHA,
Scheme 1) has recently received US Food and Drug Admin-
istration approval for the treatment of advanced cutaneous T-cell
lymphoma.[8b] An important feature of the HDAC inhibitors is
their ability to complex the zinc ion in the active site.[8d]
Itisapparentthenthatothertypesofmetalchelatorsshouldbe
investigated as alternative therapies for the removal of ferric ion
in iron overload syndromes and as potential HDAC inhibitors.
The present paper reports on a new and improved route for
the synthesis of bisamidoximes (3d–g, Scheme 2). Whereas 3a
and 3b have been previously synthesized through a seven-step
route,[9] the procedure described herein is a relatively simple
three-step route that begins with 4-methylbenzaldehyde.As ami-
doximes are known to form coloured complexes with transition
metals including iron(iii),[10,11b] the ability of these bisami-
doximes to complex with iron(iii) has also been investigated.
Although iron is essential for most forms of life, the low solu-
bility of ferric hydroxide in water has necessitated sophisticated
mechanisms for the transport and management of iron(iii) in bio-
logical systems. Microorganisms often use low molecular weight
chelators (siderophores) to solubilize and transport ferric ion.
Siderophores commonly contain the hydroxamic acid functional
group, which forms hexacoordinate, octahedral complexes with
ferric ion.[1,2]
Humans have developed a complex iron storage and recy-
cling process to supply the ferric ion necessary for proper cell
function. Unfortunately, humans afflicted with certain genetic
disorders, such as thalassemia and aplastic anemia, must receive
periodic transfusions, which lead to excess iron in the body.[3]
Excess iron in this closed metabolic loop leads to chronic over-
load and to peroxidative tissue damage. For these iron overload
syndromes, the treatment of choice has been chelation therapy.
Specifically, an open-chain siderophore (desferrioxamine B, 1,
DFO, Scheme 1), which forms a 1:1 hexacoordinate, octahedral
H
N
OH
N
O
O
O
N
N
H
N
H2N
O
O
HO
OH
1
Results and Discussion
H
O
The bisamidoximes were synthesized by treating various
diamines with a benzohydroximoyl chloride (4, Scheme 2).
The hydroximoyl chloride was prepared by reaction of a ben-
zaldoxime with N-chlorosuccinimide according to a literature
procedure.[12]
N
OH
N
H
O
2 (SAHA)
Scheme 1.
© CSIRO 2007
10.1071/CH07157
0004-9425/07/090685

686
J. E. Johnson et al.
CH3
Y
Y
W
H
N
N
N
CH3
N
H
H
N
CH3
N
N
OH
HO
OH
5
3a: Y ϭ H; W ϭ (CH2)3
b: Y ϭ H; W ϭ (CH2)4
c: Y ϭ Cl; W ϭ (CH2)3
d: Y ϭ CH3; W ϭ (CH2)2
e: Y ϭ CH3; W ϭ (CH2)3
f: Y ϭ CH3; W ϭ (CH2)4
OH
HO
N
N
CH
N
H
2 CH2
CH2 CH2
N
H
N
g: Y ϭ CH3; W ϭ (CH2)3N(CH3)(CH2)3
CH3
CH3
CH2
Cl
OH
Ether
ϩ
N
H2N
W
NH2
3c–g
CH2
N
OH
3 mol
H
N
2 mol
Y
4
a: Y ϭ Cl
b: Y ϭ CH3
CH3
6
Scheme 2.
Scheme 3.
R1
R2
N
NH
R1
O
H
R2
O
In the initial work on the present project, 4-chlorobenzo-
hydroximoylchloride4a wastreatedwith1,3-diaminopropaneto
give the bisamidoxime.The bisamidoxime 3c proved to be highly
insoluble and could not be recrystallized and further steps at
purification were abandoned. When the reaction was carried out
with 4-methylbenzohydroximoyl chloride 4b, the products were
considerably more soluble and could be purified by recrystal-
lization. Reactions of 1,2-diaminoethane, 1,3-diaminopropane,
1,4-diaminobutane, and 3,3ꢀ-diamino-N-methyl-dipropylamine
with 4-methylbenzohydroximoyl chloride 4b gave the bisami-
doximes 3d–g (Scheme 2). The reaction requires a 2:3 mol ratio
of hydroximoyl chloride to diamine. Two moles of the diamine
act as a base and form the diamine hydrochloride.
N
N
Amidoxime tautomer
N-hydroxy (or N-alkoxy) amidine tautomer
7: R1 ؍ R2 ؍ H
8: R1 ؍ H; R2 ؍ CH3
Scheme 4.
Two other amidoximes (Scheme 3) were prepared in the
presentworkbythereactionofN,N-dimethyl-1,3-diaminoethane
and tris(2-aminoethyl)amine with 4b to give the monoami-
doxime 5 and the trisamidoxime 6, respectively.
Amidoximes that have at least one hydrogen on the amide
nitrogen are capable of existing in two tautomeric forms
(Scheme 4). It is generally accepted that the oxime tautomer
is favoured.[11] It is possible to isolate the Z and E isomers of
amidoximes when the amide nitrogen is disubstituted (10 and
11, Scheme 5 for example).[13,14]
Single crystal X-ray structures of 3d, 3e, and 3f have shown
that in the crystalline state these compounds are in the ami-
doxime tautomeric form. The two amidoxime moieties in each
of these compounds have the Z configuration, with N–C=N–O
torsion angles −4.10(15)◦ in 3d, 1.2(3)◦ and −4.1(3)◦ in 3e,
and 4.62(13)◦ in 3f. Compound 3d (Fig. 1) lies on an inversion
centre in the crystal, and thus has its central N–(CH2)2–N group
fully extended. Both 3e (Fig. 2) and 3f (Fig. 3) have their central
N–(CH2)n–N groups folded, with approximate C2 symmetry for
3e and exact crystallographic C2 symmetry for 3f.
O1
N2
C2
C8
N1
C3
C4
C1
C7
C6
C5
C9
Fig. 1. ORTEP drawing of 3d, with 50% ellipsoids, showing the number-
ing scheme.
work and some other amidoximes prepared in previous work in
our laboratory (7–9, 10Z and 10E, Schemes 4 and 5).
To determine the structural requirements for complexation
of amidoximes, qualitative tests (Table 1) with iron(iii) chloride
were carried out on some amidoximes synthesized in the present
Benzamidoxime 7, as has been previously reported,
gave a burgundy colour with alcoholic ferric chloride.[11b]

Bisamidoximes
687
W
W
C1
O2
C3
N
N
O
R
C2
N
N
N3
O
R
N1
C4
C12
C14
Y
Y
C10
C13
C15
C9
C5
N4
C18
9Z: W ϭ CH(CH )CH ; Y ϭ R ϭ H
10E: W ϭ (CH ) O(CH ) ; Y ϭ Cl; R ϭ H
2 2 2 2
3
2
O1
C17
10Z: W ϭ (CH ) O(CH ) ; Y ϭ Cl; R ϭ H
11E: W ϭ (CH ) ; Y ϭ H; R ϭ CH
2 2 3
2 2
2 2
11Z: W ϭ (CH ) ; Y ϭ H; R ϭ CH
C8
2 2
3
C6
C11
C7
N2
C16
C19
Scheme 5.
Fig. 2. ORTEP drawing of 3e, with 50% ellipsoids, showing the number-
ing scheme.
ϩ
O
R
O
R
N
N
N
N
Ϫ
C2
C1
9Z: R ϭ H
11Z: R ϭ CH3
N1
Scheme 6.
C3
C4
O1
N2
C9
C7
C8
9E), the compound did not produce a colour with iron(iii).
When the amide nitrogen was a part of a six-membered ring
(morpholine)[15] (10Z), a burgundy colour was produced with
iron(iii).
C5
C10
C6
Two factors can be considered in causing this apparent dif-
ference in the ability of the amide nitrogen to complex with
iron: resonance with the imine bond and the inherent basicity
of the amide nitrogen. In previous work, we suggested that poor
overlap of the nitrogen unbonded electron pair in the aziridine
ring with the p-orbital on the oxime carbon atom is responsible
for the extraordinary resistance of 11Z and 11E to thermal Z/E
isomerization.[13b]
Fig. 3. ORTEPdrawingof 3f, with50%ellipsoids, showingthenumbering
scheme.
Table 1. Complex formation of amidoximes with
iron(iii) chloride
We suggested that the zwitterionic resonance structure
(Scheme 6) in amidoximes 11Z (and 11E) does not make as
large a contribution as it does in amidoximes with larger rings
(10Z for example). It has been suggested[16] that the downfield
chemical shift of the α-vinyl proton in N-alkenyl aziridines com-
pared with enamines derived from simple amines is due to the
decreased importance of the zwitterionic resonance form. Poor
overlap in 9Z, however, should make the electron pair on the
amide nitrogen of 9Z more available for coordination. We con-
clude that poor overlap of the amide nitrogen lone pair is not a
significant factor in determining metal ion complexation.
It is well established[17] that incorporation of a nitrogen atom
into a three-membered ring decreases the basicity of the nitrogen
atom. Aziridine has a pKb of 5.99 and the pKb of morpholine is
5.67.[18] Theoreticalcalculationshaveindicatedthatthedecrease
in basicity of aziridine is due to an increase in the pyramidaliza-
tion around the nitrogen atom.[19] It is likely that the decrease in
basicity of the nitrogen in the aziridine ring in 9Z is responsi-
ble for the inability of this amidoxime to form a complex with
iron(iii).
Amidoxime
Colour test with alcoholic
iron(iii) chloride
7
8
9
10Z
10E
Positive
Negative
Negative
Positive
Negative
O-Methylbenzamidoxime[14] 8, which has also been reported
in the literature,[11b] gave a negative test result. This is similar to
alkyl hydroxamates, which also do not form complexes with fer-
ric ion.[11b] Recent calculations[8d] on hydroxamic acids show
that a hydroxamic acid can act as bidentate ligand only when the
hydroxylamine oxygen is deprotonated. The coordination sites
are the carbonyl oxygen and the deprotonated hydroxylamine
oxygen. It seems reasonable to assume that in amidoximes, the
oxime oxygen must be deprotonated for it to act as a bidentate
ligand. The other site for coordination is likely to be the amide
nitrogen atom.
To determine the role of the amide nitrogen in complex-
ation with iron(iii), two compounds with the amide nitrogen
incorporated into a three-membered or a six-membered ring
system were tested (Scheme 5). When the amide nitrogen was
part of a three-membered ring (an aziridine ring)[13] (9Z and
Another area to consider when looking at complexes of ami-
doximes with transition metals is stereochemical effects. The
result of the ferric chloride test on the Z isomer of morpholino-
4-chlorobenzamidoxime (10Z)[15] was positive, whereas the E
(10E) failed to give a colour.
In summary, the qualitative tests of these amidoximes with
iron(iii) chloride show that the following requirements must

688
J. E. Johnson et al.
Table 2. Ratios of ligand to iron(iii) from Job’s plots in aceto-
be met in order for an amidoxime to act as a chelating
agent: (i) the hydroxylamine oxygen must be unsubstituted;
(ii) the amidoxime must be in the Z configuration; and (iii) the
amide nitrogen of the amidoxime cannot be incorporated into a
three-membered ring.
Job’s method of continuous variations, a commonly
used method for determining compositions of complexes in
solution,[20] was used to determine the stoichiometry of the com-
plexes formed by the reaction of amidoximes with iron(iii). The
method is carried out in a batch mode by mixing aliquots of two
equimolar stock solutions of metal and ligand. The solutions are
prepared in such a manner that the total molar concentration of
metal plus ligand is kept constant while the ligand-to-metal ratio
varies from flask to flask, that is:
nitrile
C, curved plot; I, intersecting lines
Ligand
Total conc.
of ligand and
iron(iii) [M]
Job’s plot max.
(ratio of ligand
to iron(iii))
Type of
plot
λmax
[nm]
5
5
0.0040
0.0020
0.0040
0.0020
0.0016
0.0020
0.0020
0.00080
0.0020
0.00080
0.0020
0.00080
0.00160
0.67 (2:1)
0.67 (2:1)
0.50 (1:1)
0.50 (1:1)
0.67 (2:1)
0.67 (2:1)
0.50 (1:1)
0.50 (1:1)
0.67 (2:1)
0.50 (1:1)
0.50 (1:1)
0.50 (1:1)
0.67 (2:1)
C
C
C
C
C
C
C
C
C
C
I
533
533
520
520
500
500
525
525
550
550
540
540
465
3d
3d
3e
3e
3f
3f
3g
3g
5
CM + CL = k,
where CM and CL are the analytical concentrations of metal
and ligand, respectively, and k is a constant. The corrected
absorbance, the measured absorbance at a given wavelength
minus the absorbance of the metal in the absence of ligand, is
plotted as a function of mole fraction of ligand. The resulting
curves (Job’s plots) show a maximum absorbance that yields the
ligand-to-metal ratio of the complex in solution.[20] Job’s plots
forbenzamidoxime 7[10f] havebeenreportedforcobalt(ii), butto
our knowledge, no other reports on continuous variation studies
of amidoximes have been reported.
The continuous variations data, obtained at 533 nm in
dimethylformamide (DMF), is given for benzamidoxime 7 with
iron(iii) in tables 12S and 13S in the Accessory Publication.
When the data is plotted (figs 12S and 13S in the Accessory
Publication), an absorbance maximum appears at a ligand mole
fraction of 0.67, which indicates a 2:1 ligand-to-metal ratio in
the complex. This result suggests that benzamidoxime is acting
as a bidentate ligand. The fact that the plot is a curve rather than
two intersecting straight lines is an indication that the formation
constant for this complex is not high (Kf < 1.4 × 102).[20]
Tables in theAccessory Publication give the continuous varia-
tionsdataobtainedinDMFfortheotherbisamidoximesprepared
in the present work. Table 2 contains a summary of the continu-
ous variation experiments carried out on benzamidoxime and
the new amidoximes prepared in the present work. Three of
the bisamidoximes (3d, 3f, and 3g) prepared in this work form
complexes in a 1:1 ligand-to-metal ratio. This indicates that the
bisamidoximes 3d, 3f, and 3g are acting as tetradentate ligands.
5
6
I
I
NMR spectra were determined on a Varian Mercury 300 MHz
or aVarian EM 390 90 MHz spectrometer. High-resolution mass
spectra were determined on a BioTOF II ESI Instrument. Mid-
west Microlab (LLC, Indianapolis, IN, USA) performed the
elemental analysis of the new compounds. All chemicals used in
this work were purchased from Aldrich Chemical Co., and were
at least 98% pure.
Crystal Structure Determinations
The structures of compounds 3d, 3e, and 3f were determined,
using data collected at low temperature with MoKα radiation
(λ 0.71073 Å) on a Nonius KappaCCD diffractometer. Crystal
data for 3d: C18H22N4O2, MW 326.40, monoclinic, space group
P21/n, a 5.6466(5), b 8.5760(10), c 17.919(2) Å, β 98.997(7)◦,
V 857.06(16) Å3, Z 2, T 110 K, Dx 1.265 g cm−3, µ 0.85 cm−1
,
colourless needle with dimensions 0.50 × 0.25 × 0.23 mm3,
23 244 measured data with θ <30.8◦, 2667 unique data used
in refinement, R 0.046 for 2135 observed data, 116 refined
parameters. Crystal data for 3e: C19H24N4O2, MW 340.42,
monoclinic, space group P21/c, a 18.220(6), b 7.185(3), c
14.269(5) Å, β 108.92(2)◦, V 1767.0(11) Å3, Z 4, T 220 K,
Dx 1.280 g cm−3, µ 0.85 cm−1, colourless plate with dimen-
sions 0.47 × 0.22 × 0.12 mm3, 9260 measured data with θ
<25.4◦, 3215 unique data used in refinement, R 0.046 for
2072 observed data, 241 refined parameters. Cooling to lower
temperatures led to destruction of the crystal, an apparent
result of a phase change. Crystal data for 3f: C20H26N4O2,
MW 354.45, monoclinic space group C2/c, a 19.854(2), b
7.1601(10), c 13.514(2) Å, β 106.463(9)◦, V 1842.3(4) Å3, Z
4, T 110 K, Dx 1.278 g cm−3, µ 0.85 cm−1, colourless blade
fragment with dimensions 0.50 × 0.50 × 0.12 mm3, 18 500 mea-
sured data with θ <30.6◦, 2793 unique data used in refinement,
R 0.042 for 2284 observed data, 126 refined parameters. The X-
ray crystallographic data have been deposited in CIF format as
CCDC-637298, 637299, 637300, available from the Cambridge
Crystallographic Data Centre.
Conclusions
A relatively simple three-step synthesis from 4-methylbenzalde-
hyde has been developed for the preparation of bisamidoximes.
Four new bisamidoximes have been prepared using this method.
Single crystal X-ray structure determinations on three of the
bisamidoximes shows that both amidoxime moieties exist in the
Z configuration.The structural requirements for complex forma-
tion with iron(iii) have been determined. One trisamidoxime and
one new monooxime containing an amine functional group also
have been prepared in the present work. Job’s method of contin-
uous variations has shown that three of the bisamidoximes act
as tetradentate ligands with iron(iii).
Experimental
Synthetic Experimental Procedures
General Procedures
4-Methylbenzohydroximoyl Chloride 4b
Melting points were determined in a Mel-Temp capillary melt-
ing point apparatus and are uncorrected. Proton and carbon
4-Methylbenzaldehyde oxime (15.0 g, 0.111 mol) was dis-
solved in DMF (90 mL) at 25–30◦C followed by the addition of

Bisamidoximes
689
1/5 of the solid N-chlorosuccinimide (15.0 g, 0.112 mol) while
stirring.The reaction was then kept below 35◦C by the rate of the
addition of the N-chlorosuccinimide and intermittent cooling in
an acetone/dry ice bath. Completion of the reaction was noted by
the cessation of the exotherm. The solution was poured into four
volumes of ice water and extracted with ether (2 × 200 mL). The
combined ether extracts were then washed with ice-cold water
(2 × 200 mL). The organic layer was dried over magnesium sul-
fate and the ether removed by rotary evaporation at aspirator
pressure to yield pale yellow crystals (17.0 g, 0.100 mol, 90%).
The crude hydroximoyl chloride was used for the conversion
to the bisamidoxime without further purification: mp 70–72◦C
(68–71◦C).[12] δH (90 MHz, CDCl3) 2.35 (3H, s), 7.18 (2H, d),
7.70 (2H, d), 9.05 (1H, s).[12]
42.7, 127.9, 128.8, 129.9, 138.2, 154.9. νmax (KBr)/cm−1 3395,
3243, 1638.
1,7-Bis[Nꢀ-(Z)-4-methylbenzene-N-
hydroxycarboximidamido]-N-methyl-4-azaheptane 3g
3,3ꢀ-Diamino-N-methyldipropylamine (4.88 g, 0.0336 mol)
in anhydrous ether (100 mL) was stirred in an ice bath at <5◦C
during the dropwise addition of 4-methylbenzohydroximoyl
chloride (3.80 g, 0.0224 mol) dissolved in ether (40 mL). After
completion of the addition, the solution was stirred at room tem-
perature for 1 h, during which time a beige semi-solid formed.
Enough water was added to the solution to dissolve the pre-
cipitate. An open Erlenmeyer flask containing the ether/water
mixture was allowed to stand in the hood until dense crystals
formed at the interface and fell to the bottom of the flask.
The liquid was then decanted from the crystals and they were
recrystallized from an ethanol/water solution to yield colourless
crystals (1.43 g, 17%). mp 118–119.5◦C. (Found: C 67.1, H 8.0,
N 17.0, M+• + H 412.270. C23H33N5O2 requires C 67.1, H 8.1,
N 17.0%, M+• + H 412.2707). δH (300 MHz, CDCl3) 1.53 (4H,
quintet, J 7), 2.09 (3H, s), 2.29 (4H, t, J 7), 2.36 (6H, s), 3.04
(4H, s with shoulders), 5.65 (2H, br s), 7.17 (4H, d, J 8), 7.35
(4H, d, J 8). δC (300 MHz, CDCl3) 21.3, 28.4, 41.8, 42.2, 55.2,
128.4, 128.8, 129.0, 139.3, 156.8. νmax (KBr)/cm−1 3374, 3214,
1620. λmax (ethanol)/nm 258 (3.81).
1,2-Bis[Nꢀ-(Z)-4-methylbenzene-N-
hydroxycarboximidamido]ethane 3d
1,2-Diaminoethane (1.77 g, 0.0295 mol) in anhydrous ether
(100 mL) was stirred in an ice bath at <5◦C during the drop-
wise addition of 4-methylbenzohydroximoyl chloride (5.00 g,
0.0295 mol) dissolved in ether (40 mL). After completion of
the addition, the solution was then stirred at room temperature
for 1 h, and during this time a colourless precipitate formed.
The solution was filtered and the solid was recrystallized from
ethanol/water (1.87 g, 60%). mp 204◦C (dec.). (Found: C 66.2,
H 6.9, N 17.1. C18H22N4O2 requires C 66.2, H 6.8, N 17.2%). δH
(300 MHz, d6-DMSO) 2.33 (6H, s), 2.89 (br d, J 6, 4H), 5.74 (br
t, J 7, 2H), 7.17 (8H, s), 9.68 (2H, s). δC (300 MHz, d6-DMSO)
20.9, 44.0, 128.0, 128.7, 129.6, 138.2, 154.5. νmax (KBr)/cm−1
3380, 3119, 1651. λmax (ethanol)/nm 255 (8.54).
(Z)-N-Hydroxy-Nꢀ-(2-N,N-dimethylaminoethyl)-
4-methylbenzenecarboximidamide 5
N,N-Dimethyl-1,3-diaminoethane (5.20 g, 0.0590 mol) in
anhydrous ether (100 mL) was stirred in an ice/water bath at
<5◦C
during
the
dropwise
addition
of
the
4-methylbenzohydroximoyl chloride (5.00 g, 0.0295 mol) dis-
solved in ether (40 mL). After completion of the addition, the
solution was then stirred at room temperature for 1 h; during
this time a colourless precipitate formed. The solution was then
filtered, and the filtrate was decolourized with activated charcoal
yielding a colourless solution. The ether solution was allowed to
sit overnight to concentrate the solution, yielding large colour-
less crystals, which were then recrystallized from ether/hexanes
(5.34 g, 82%). mp 97–98◦C. (Found C 65.1, H 8.6, N 19.0.
C12H19N3O requires C 65.1, H 8.7, N 19.0%). δH (300 MHz,
d6-DMSO) 2.07 (6H, s), 2.24 (2H, t, J 6), 2.32 (3H, s), 2.96 (2H,
q, J 6), 5.70 (1H, t, J 6), 7.21 (2H, d, J 8), 7.31 (2H, d, J 8), 9.65
(1H, s). δC (300 MHz, d6-DMSO) 20.8, 40.8, 45.0, 59.4, 128.0,
128.7, 129.9, 138.3, 154.6. νmax (KBr)/cm−1 3347, 2955, 1632.
λmax (ethanol)/nm 257 (3.66).
1,3-Bis[Nꢀ-(Z)-4-methylbenzene-N-
hydroxycarboximidamido]propane 3e
1,3-Diaminopropane (4.40 g, 0.0593 mol) in anhydrous ether
(100 mL) was stirred in an ice water bath at <5◦C during
the dropwise addition of 4-methylbenzohydroximoyl chloride
(5.00 g, 0.0260 mol) dissolved in ether (40 mL). After com-
pletion of the addition, the solution was then stirred at room
temperature for 1 h and during this time a colourless precipitate
formed. The mixture was then filtered and the colourless solid
was recrystallized from ethanol/water (1.23 g, 25%). mp 110–
112.5◦C. (Found: C 66.5, H 7.2, N 16.4. C19H24N4O2 requires C
67.0, H 7.1, N 16.5%). δH (300 MHz, d6-DMSO) 1.37 (quintet,
J 6.7, 2H), 2.30 (s, 6H), 2.86 (4H, q, J 6.7), 5.66 (1H, t, J 6.6),
7.16 (4H, d, J 8), 7.23 (4H, d, J 8), 9.62 (2H, s). δC (300 MHz, d6-
DMSO) 20.9, 32.7, 40.3, 127.9, 128.8, 129.8, 138.2, 154.7. νmax
(KBr)/cm−1 3405, 3254, 1638. λmax (ethanol)/nm 258 (3.83).
Synthesis of the Trisamidoxime 6
Tris(2-aminoethyl)amine (3.60 g, 0.0245 mol) in anhydrous
ether (75 mL) was stirred in an ice bath at <5◦C during the drop-
wise addition of 4-methylbenzohydroximoyl chloride (3.00 g,
0.0177 mol) dissolved in ether (30 mL). After completion of the
addition, the solution was stirred at room temperature for 1 h,
during which time a solid formed. The ether was then decanted
from the precipitate and the precipitate was recrystallized from
an ethanol/water solution to yield colourless crystals (0.54 g,
17%). mp 178–179◦C. (Found: C 66.2, H 7.2, N 17.9, M+• + H
546.3204. C30H39N7O3 requires C 66.0, H 7.2, N 18.0%,
M+• + H 546.3187). δH (300 MHz, d6-DMSO) 2.17 (6H, t, J
6.3), 2.32(9H, s), 2.77(6H, q, J6.3), 5.63(3H, t, J6.6), 7.18, 7.23
(12H, dd, J 8.4), 9.63 (3H, s). δC (300 MHz, d6-DMSO), 20.9,
41.0, 54.9, 127.9, 128.8, 129.8, 138.2, 154.5. νmax(Nujol)/cm−1
3396, 3355, 3106(br), 1634. λmax (ethanol)/nm 258 (3.81).
1,4-Bis[Nꢀ-(Z)-4-methylbenzene-N-
hydroxycarboximidamido]butane 3f
1,4-Diaminobutane (4.00 g, 0.0454 mol) in anhydrous ether
(100 mL) was stirred in an ice bath at <5◦C during the drop-
wise addition of 4-methylbenzohydroximoyl chloride (5.10 g,
0.0301 mol) dissolved in ether (40 mL). After completion of the
addition, the solution was stirred at room temperature for 1 h, and
duringthistimeacolourlessprecipitateformed.Thesolutionwas
then filtered and the solid was isolated and recrystallized from
ethanol/water (4.10 g, 77%). mp 186.5–187◦C. (Found: C 67.7,
H 7.5, N 15.8. C20H26N4O2 requires C 67.8, H 7.4, N 15.8%).
δH (300 MHz, d6-DMSO) 1.23 (4H, br s), 2.32 (6H, s), 2.82 (4H,
d with shoulders, J 6), 5.57 (2H, t, J 6.6), 7.24 (4H, d, J 8), 7.18
(4H, d, J 8), 9.65 (2H, s). δC (300 MHz, d6-DMSO) 20.9, 27.9,

690
J. E. Johnson et al.
(Z)-Morpholino-4-chlorobenzamidoxime 10Z
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Med. Chem. Lett. 2007, 17, 2216. doi:10.1016/J.BMCL.2007.01.117
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Ulrich, Bioorg. Med. Chem. Lett. 2007, 17, 2874. doi:10.1016/J.
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4-Chlorobenzohydroximoyl chloride (5.0 g, 0.03 mol) in dry
benzene was added to dry morpholine (5.2 g, 0.06 mol) also in
dry benzene at 0–5◦C. After stirring for 30 min, the precipitated
morpholine hydrochloride was filtered off and washed with dry
benzene until colourless. The combined benzene washings were
evaporated under vacuum at room temperature and the resultant
yellowsolidwasrecrystallizedfromchloroform/pentaneatroom
temperature (5.54 g, 85%). mp 132–137◦C (110–112◦C).[15]
(d) D. Wang, P. Helquist, O. Wiest, J. Org. Chem. 2007, 72, 5446.
doi:10.1021/JO070739S
[9] (a) L.-C. Xu, M. Nakayama, K. Harada, H. Nakayama, S. Tomiguchi,
A. Kojima, M. Takahashi, Y. Arano, Nucl. Med. Biol. 1998, 25, 295.
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(b) L.-C. Xu, M. Nakayama, K. Harada, A. Kuniyasu, H. Nakayama,
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1999, 10, 9. doi:10.1021/BC980024J
(E)-Morpholino-4-chlorobenzamidoxime 10E
Crystals of 10Z were allowed to stand at room temperature
forseveraldaystoensurecompleteisomerizationtotheEisomer.
mp 132–137◦C (lit.[14] 110–112◦C).
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doi:10.1021/AC50056A044
Accessory Publication
Accessory publications for the Job’s plots are available from
the authors or from the Australian Journal of Chemistry until
September 2011.
(d) M. W. Wehking, R. T. Pflaum, E. S. Tucker, Anal. Chem. 1966, 38,
1950. doi:10.1021/AC50155A077
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Acknowledgements
We acknowledge the NIH/NIGMS MBRS Grant R25-GM55380, The
RobertA.WelchFoundation(Grantno. M-0200), theTexasHigherEducation
Coordinating Board–Advanced Research Program (Grant no. 003646–
0002), and the Texas Woman’s University Research Enhancement Program
for support of this work. We also thank Melissa Bodnar, Xuan Thao Nghe,
and Aungeleca Williams who made the measurements for the Job’s plot on
compound 6 as part of their instrumental analysis class.
(b) P. A. S. Smith, Open-Chain Organic Nitrogen Compounds 1966,
Vol. 2, pp. 35, 73–74, 76, 84, 85, 92 (Benjamin: New York, NY).
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doi:10.1021/JO01307A039
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N. Sanchez, J. Heterocycl. Chem. 1996, 33, 1583.
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[14] J. E. Johnson, S. C. Cornell, J. Org. Chem. 1980, 45, 4144.
doi:10.1021/JO01309A015
[15] K. Dignam, A. Hegarty, P. Quain, J. Chem. Soc. Perkin Trans. 2 1977,
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[16] S. Dalili, A. K. Yudin, Org. Lett. 2005, 7, 1161. doi:10.1021/
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